Background/purpose: In the murine nitrofen-induced model of congenital diaphragmatic hernia (CDH), the lungs are primarily hypoplastic and immature even before diaphragmatic closure. Because excess transforming growth factor-beta (TGF-beta) signaling induces pulmonary hypoplasia, the authors hypothesized that primary hypoplasia after nitrofen exposure may be caused by aberrant signaling by the TGF-beta pathway. Therefore, abrogation of TGF-beta signaling might rescue the hypoplasia.
Methods: The authors performed intratracheal microinjections of a recombinant adenoviral vector encoding a dominant-negative TGF-beta type II receptor (AdIIR-DN) in nitrofen-exposed and control E12 mouse lungs, which then were cultured for 4 days in serumless chemically defined media. The mRNA expression of Smad2, 3, 4, and 7 in nitrofen-exposed and control E12 lungs after 4 days in culture were compared.
Results: ADIIR-DN increased terminal branching in control lungs by 28% compared with lungs injected with control virus (61.8 +/- 4.6 v. 48.4 +/- 4.7, P =.004). However, there was no difference between nitrofen-exposed lungs injected with ADIIR-DN and those injected with control virus. Compared with control lungs, Smad mRNA expression was decreased markedly in nitrofen-exposed lungs: Smad2 (40%, P =.16), Smad3 (29%, P =.02), Smad4 (25%, P =.07), and Smad7 (36%, P =.04).
Conclusions: Because abrogation of TGF-beta signaling does not rescue the hypoplasia seen in the nitrofen model, and Smad expression is decreased in nitrofen-exposed lungs, the TGF-beta pathway does not appear to play a role in nitrofen-induced pulmonary hypoplasia.
Copyright 2002, Elsevier Science (USA). All rights reserved.